Purpose :
Much of the vision loss in the common blinding eye disease wet age-related macular degeneration (AMD) is due to neovascularization of the choroid. No small molecule pharmacotherapies are yet approved for this disease. We previously identified the heme biosynthesis enzyme ferrochelatase as an important mediator of ocular neovascularization; knockdown of ferrochelatase blocked angiogenesis in vitro and in the murine laser-induced choroidal neovascularization (L-CNV) model. Small molecule inhibition of ferrochelatase is thus an appealing approach for impeding neovascularization. Excitingly, the FDA-approved antifungal drug griseofulvin inhibits ferrochelatase as an off-target effect. Hence, here we sought to investigate if griseofulvin can block angiogenesis.

Methods :
The anti-angiogenic effects of griseofulvin and its active metabolite, N-methylprotoporphyrin (NMPP), were tested in vitro using proliferation, scratch-wound migration, and tube formation assays with human retinal endothelial cells. The choroidal sprouting assay assessed griseofulvin’s effects on choroidal cells ex vivo. The murine L-CNV model was used to test the in vivo anti-angiogenic potential of griseofulvin, delivered intravitreally or orally. L-CNV was analyzed both in vivo by optical coherence tomography, and ex vivo by confocal microscopy.

Conclusions :
Griseofulvin at clinically achievable concentrations has significant anti-angiogenic potential in the eye. Since oral griseofulvin is already approved for human use and well tolerated during long-term administration, these findings could progress rapidly toward human trials, with potential benefit for the sight of wet AMD patients and applicability to other ocular neovascular diseases.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.